To begin the 2005–06 campaign, Pominville had initially been waived by the Sabres. Clearing waivers, he continued to play in the minors until he was called up a few months into the season.[2] He scored his first NHL goal on November 27, 2005 – a powerplay goal against Olaf Kölzig in a 3–2 win against the Washington Capitals.[3] Pominville quickly became an integral part of the Sabres line-up and finished the rest of the season with the Sabres with 18 goals in 57 games. In the 2006 playoffs, he recorded a hat-trick in Game 2 of the first round against the Philadelphia Flyers.[4] Later in the Sabres' playoff run, he scored the series-clinching goal in the second round against the Ottawa Senators – a shorthanded effort in overtime of Game 5.[5] It marked the first time in NHL history that a playoff series was decided by an overtime shorthanded goal.[citation needed] Buffalo announcer Rick Jeanneret marked this occasion with a call that is now famous in Buffalo hockey lore: "Oh, now do you believe? Now do you believe? These guys are good, scary good!" The Sabres had qualified as the fourth seed in the playoffs after failing to qualify the previous three seasons.

After improving to 68 points the following season, Pominville made a name for himself in 2007–08. He scored at nearly a point-per-game with 80 points in 82 games. In the absence of departed co-captains Chris Drury and Daniel Brière from the previous season, the Sabres utilized a rotating captaincy during the 2007–08 season; Pominville was named captain for the months of March and April.[2] At the end of the season, he was nominated for the Lady Byng Memorial Trophy as the league's most sportsmanlike player, along with Pavel Datsyuk and Martin St. Louis;[6] the honour was awarded to Datsyuk.

On September 18, 2008, the Sabres acknowledged Pominville's rise to prominence and signed him to a five-year, $26.5 million contract extension (taking effect in 2009–10). His existing contract saw him make just over $1 million per season.[2]

On October 13, 2010, his consecutive start streak of 335 games was broken because of the concussion he had received from Chicago Blackhawks defensemen Niklas Hjalmarsson (who was suspended two games for the illegal hit) in the previous game on October 11, 2010, when he was checked into the boards head first and then removed from the ice in a stretcher.[7]

On October 6, 2011, in Helsinki, Finland, Pominville was named permanent Sabres captain. He became the 16th full-time captain in Sabres team history.[8]

With the lockout postponing the beginning of the 2012–13 season, Pominville signed his first European contract on a temporary basis with German club Adler Mannheim of the Deutsche Eishockey Liga on November 30, 2012.[9] Pominville produced 12 points in just seven games for the Eagles before returning to prepare for the Sabres' season opener.

With the Sabres enduring a largely unsuccessful season and with the intentions to revamp the roster, Pominville was dealt at the trade deadline, along with a fourth-round pick in 2014, to the Minnesota Wild in exchange for prospects Johan Larsson, Matt Hackett and two draft picks: a first-rounder in 2013, and a second-rounder in 2014 on April 3, 2013.[10][11] During the 2013–14 season, he scored 30 goals and 30 assists for 60 points to lead the Wild in scoring.